Heart disease remains the number one killer in the United States. The majority of these deaths occur suddenly as the result of lethal ventricular tachyarrhythmias. There is growing evidence that malignant arrhythmias in these patients are a consequence of altered ventricular repolarization. The central hypothesis of this research program is that lability in ventricular repolarization duration, or the electrocardiographic QT interval, provides a non-invasive measure of electrical instability. This proposal includes one set of aims to study mechanisms of repolarization lability, and another set of aims testing the clinical utility of beat-to-beat QT interval variability measurements. We will determine the role of autonomic regulation in the genesis of repolarization changes by studying the effects of selective autonomic blockade on QT interval variability in patients undergoing clinical electrophysiologic study. In some patients, we will also record monophasic action potentials from multiple endocardial sites to establish whether repolarization lability is a focal or diffuse phenomenon. These measurements will be repeated in a subset of patients who will receive intravenous ibutilid3e to provoke early after-depolarizations and ventricular pro-arrhythmia. The long-term predictive value of QT variability measurement will be tested prospectively in a large cohort of patients with ischemic and non- ischemic dilated cardiomyopathy. In addition, we will test the short-term predictive significance of increased QT variability in hospitalized patients in the Cardiac Care Unit and in ambulatory patients with implantable cardioverter defribllators (ICDs) who experience malignant ventricular arrhythmias. Finally, patients undergoing coronary angioplasty will be studied to determine the effects of acute myocardial ischemia on QT interval variability. This work should enhance our understand of arrhythmia mechanisms that cause sudden cardiac death and our ability to predict its occurrence.